Biochemical and Immunological Mechanisms Underlying Differential Interaction of Superantigens with Host Immunogenetic Factors in Streptococcal Sepsis

Abstract

DEDICATIONTo my loving and encouraging parents The Strep SAgs include the streptococcal pyrogenic exotoxins (Spes), which play a crucial role in the pathogenesis of severe invasive streptococcal diseases, including Strep toxic shock syndrome (STSS). However, not all septic individuals infected with SAgproducing GAS develop STSS. Our epidemiologic studies showed that individual HLA class II allelic variation plays a crucial role in modulating the severity of invasive GAS diseases. Certain HLA class II alleles and haplotypes confer strong protection from STSS (DRB1*1501/DQB1*0602) or increase the risk for it (DRB1*1401/DQB1*0503 and DRB1*0701/DQB1*0202), whereas others behave in a neutral fashion with respect to disease severity. The main aim of this thesis was to validate the direct role of HLA class II variation in modulating the severity of GAS sepsis and investigate molecular mechanisms underlying the differential effect of HLA class II variation on SAgs responses in vitro and in vivo.We validated our epidemiological findings and confirmed the direct role of HLA class II allelic variation in modulating the severity of GAS sepsis using HLA transgenic In conclusion, our study demonstrates a dominant and direct role of HLA class II in controlling Strep SAgs responses and resulting disease severity. The data indicate that each SAg-class II allele is unique with distinct behavior that cannot be extrapolated to others. Future studies will investigate this point further and determine the interactions between high risk and protective HLA class II alleles, when expressed on the same APC.x